Mice Make Their Own Morphine

Illicit drug use and poppy seed bagels may not be the only sources of opioids that turn up in people’s urine.

Mammals make their own morphine, a new study shows.

Scientists have known for decades that people excrete some morphine in their urine, but most people assumed that the pain-killing drug came from the diet or drug use. A new study shows that mice, and probably humans and other mammals, can make morphine from scratch.

“This paper now really shows that the whole pathway [to synthesize morphine] operates in the mouse,” says Heinz Floss, an emeritus biochemist at the University of Washington in Seattle who was not involved in the work. The study, published online the week of April 26 in the Proceedings of the National Academy of Sciences, also shows that the body rapidly uses up morphine’s building blocks by breaking them down or converting them to other chemicals, which helps explain why it has been difficult to determine whether people make the compound, says Floss.

No one yet knows why the body makes morphine, but researchers suspect it could be a natural painkiller or perhaps is used to help nerve cells communicate with each other. Where the morphine is made also remains a mystery.

To learn whether mammals can synthesize morphine, researchers led by Meinhart Zenk, a biochemist at the Donald Danforth Plant Science Center in St. Louis, injected a mouse over the course of four days with a chemical called tetrahydropapaveroline, or THP. The compound is found naturally in human brain cells and is one of the chemicals that is altered to build morphine in plants.

Using a supersensitive mass spectrometry instrument that precisely elucidates a molecule’s chemical composition, the researchers found that the mouse metabolized most of the THP into several different chemicals including salutaridine. In morphine-producing poppy plants salutaridine is then converted to thebaine, which undergoes further reactions to become morphine. The researchers show that mice can also do that chemical conversion, as well as others needed to generate morphine.

The earliest stages of the morphine production pathway differ slightly between plants and animals, the team found. Those differences show that “morphine has obviously been discovered twice in evolution,” Zenk says.

Floss thinks more data is needed to determine whether plants and animals independently evolved the intricate, multistep biochemical pathways used to make morphine, or if the synthesis pathway was already present in ancient ancestors of both plants and animals and has been modified since the two kingdoms split.

Now that scientists know mammals can make morphine, the challenge will be to figure out what purpose the compound serves, Zenk says. He and his colleagues want to pinpoint where in the body morphine is made and learn whether it plays a role in regulating pain.

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